In vitro studies demonstrate that N-demethylation of amitriptyline to nortriptyline is mediated mainly by cytochrome P450-3A4, while hydroxylation of amitriptyline to 10-hydroxy-amitriptyline is mediated in part by P450-2D6. These data predict the possibility of impaired clearance of amitriptyline in vivo by coadministration of ketoconazole or quinidine, highly active and relatively specific competitive inhibitors of 3A4 and 2D6, respectively. This hypothesis will be tested in two prospective double-blind controlled kinetic-dynamic studies.